PROJECT SUMMARY/ ABSTRACT Tremor is the most common movement disorder and is often highly disabling. How these rhythmic movements are generated from the abnormal brain circuitry is still poorly understood. Among tremor disorders, essential tremor (ET) is the most common and a prototypical disorder for tremor. Recent postmortem human pathology studies have shown that ET might be a disease of cerebellar synaptic pathology. Specifically, there is abnormal synaptic formation between climbing fibers (CFs) and Purkinje cells (PCs) in the cerebellar cortex of ET patients. To further investigate the pathophysiology between this PC synaptic pathology and tremor, we established a mouse model with ET-like PC synaptic pathology and found that this mouse model develops age-related kinetic tremor that responds to primidone, propranolol, and alcohol, similar to ET patients. However, the detailed pathophysiology remains obscure. Therefore, we propose a series of experiments to study the relationship between PC synaptic pathology, PC physiology and tremor in this novel mouse model. In Specific Aim 1, we will use optogenetic approaches to inhibit PC activities in our novel tremor mouse model and observe whether tremor could be suppressed. In addition, we will optogenetically enhance PC activities at different frequencies and observe whether this manipulation will create tremor in wild type mice. In Specific Aim 2, we will determine how the PC synaptic pathology interacts with PC degenerative changes, which could modulate tremor characteristics (frequency and amplitude) and the corresponding cerebellar physiology in our tremor mouse model during tremor onset and tremor progression. In Specific Aim 3, we will manipulate molecules controlling PC synaptic organization to pinpoint how specific PC synaptic pathology and PC physiology can regulate tremor. We have developed methods to study anatomical PC synaptic organization and to simultaneously record PC responses during tremor in freely moving mice, which will allow us to perform detailed examination of how the PC activity relates to tremor characteristics. Our study will thus provide important insights into the pathophysiology of tremor.